PROJECT SUMMARY/ABSTRACT The long-term career goal of the candidate is to identify treatment strategies for common medical conditions that have beneficial impacts on brain health in late-life. The short-term career objectives of the candidate are to: develop key research skills in causal inference methods, gain a basic understanding of dementia-related neuropathology, learn about the diagnosis of dementia and neuropsychological testing in clinical care, and develop communication skills and build strong foundations for local and national leadership. Successful completion of the proposed research and career development program will position the candidate to become an independent investigator and national leader in dementia pharmacoepidemiology ? an area of great opportunity for discovery. In part, this will be accomplished through coursework, mentored learning experiences, and research-related activities. These experiences will allow the candidate to gain practical skills that can be directly applied to the proposed K76 research to enhance research productivity. The Paul B. Beeson Emerging Leaders Career Development Award in Aging would provide the necessary resources, training, and mentoring to achieve these career goals and objectives. The long-term objective of this proposed research is to prevent or delay dementia using brain-protectant antihypertensives. The specific aims of this research are to: 1) test the hypothesis that after controlling for their effects on blood pressure, exposure to Angiotensin (Ang)-II# drugs (compared with Ang-II$ drugs) will be associated with lower risk of Alzheimer?s Disease (AD) and non-AD dementias; and 2) test whether, after controlling for their effects on blood pressure, exposure to Ang-II# drugs (compared with Ang-II$ drugs) will have an independent association with standard markers of neuropathology, including Braak stage, CERAD level, cystic infarcts, microinfarcts, and Lewy bodies, as well as highly quantitative measures of neurotoxic peptides, inflammation, and gliosis using a multiplexed Histelide assay, and increase resilience to the effects of neuropathology, such that the association between these neuropathology measures and dementia outcomes will be weaker. Aim 1 may help guide treatment of hypertension in adults to optimize brain health. Aim 2 will provide evidence to understand the biological basis of any association between antihypertensives and dementia. In summary, this Beeson K76 proposal outlines training and mentored research activities to support the career development of Zachary A. Marcum, PharmD, PhD toward his goal of becoming an independently- funded translational scientist researching methods to improve brain health for older adults. The Department of Pharmacy at the University of Washington and the Kaiser Permanente Washington Health Research Institute will provide a rich environment for the candidate.